chr1-37537804-T-C

Variant names:

• chr1-37537804-T-C
• rs866874156
• NM_024700.4:c.1135A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_024700.4(SNIP1):​c.1135A>G​(p.Ile379Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SNIP1 NM_024700.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.83

Genes affected

SNIP1 (HGNC:30587): (Smad nuclear interacting protein 1) This gene encodes a protein that contains a coiled-coil motif and C-terminal forkhead-associated (FHA) domain. The encoded protein functions as a transcriptional coactivator that increases c-Myc activity and inhibits transforming growth factor beta (TGF-beta) and nuclear factor kappa-B (NF-kB) signaling. The encoded protein also regulates the stability of cyclin D1 mRNA, and may play a role in cell proliferation and cancer progression. Mutations in this gene are a cause of psychomotor retardation, epilepsy, and craniofacial dysmorphism (PMRED). [provided by RefSeq, Mar 2012]

LOC105378649 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025028706).
• BP6: Variant 1-37537804-T-C is Benign according to our data. Variant chr1-37537804-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1373159.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNIP1	NM_024700.4	c.1135A>G	p.Ile379Val	missense_variant	Exon 4 of 4	ENST00000296215.8	NP_078976.2
LOC105378649	XR_947190.3	n.621-885T>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNIP1	ENST00000296215.8	c.1135A>G	p.Ile379Val	missense_variant	Exon 4 of 4	1	NM_024700.4	ENSP00000296215.5
SNIP1	ENST00000638725.1	n.1647A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2
SNIP1	ENST00000468040.2	n.*909A>G		downstream_gene_variant		5		ENSP00000492185.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1112012

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Jul 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 379 of the SNIP1 protein (p.Ile379Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SNIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1373159). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Oct 20, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.58
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.059
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.025
MutPred		0.13		Loss of helix (P = 0.1706);
MVP		0.10
MPC		0.48
ClinPred		0.039	T
GERP RS		4.2
Varity_R		0.013
gMVP		0.16
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs866874156; hg19: chr1-38003405;